The research goal of this application is to initiate studies to identify specific innate immune receptors, including toll-like receptors (tlr) that are activated by filarial and Wolbachia products. Additionally, early immune effector molecules involved in the inflammatory response, such as cytokines and chemokines, will be identified. Initial laboratory studies will utilize transfected cell lines and animal models to identify important receptor pathways. Later work will confirm the mechanism of recognition and response to filarial and Wolbachia products in human disease using peripheral blood monocytes from humans infected with Wuchereria bancrofti in Papua New Guinea. Training in laboratory techniques, research methodology and ethics, field based research and clinical tropical medicine will be important components of the project. Wolbachia are obligatory intracellular bacteria that infect all filarial species of medical significance. Recent observations indicate that lipopolysaccharide (LPS)-Iike products of Wolbachia endosymbionts induce acute inflammatory responses in the mammalian host. Preliminary studies using CD14+ monocytes from filadae-naive humans indicate that B. malayi extracts stimulate TNF-alpha, IL-6, and IL-10 production. In contrast, Acanthocheilonema viteae, a filarial parasite not infected with Wolbachia, or B. malayi treated with doxycycline stimulate little to no cytokine production by monocytes. Experiments using transfected cell lines expressing human toll-like receptors and monocytes exposed to B. malayi extracts with competitive inhibitors of the LPS - TLR4 interaction suggest that the stimulatory effects of Brugia are exerted through both TLR4 and TLR4-independent pathways. However, differences and similarities of receptors involved in recognition of nematode versus Wolbachia ligands have not yet been identified. The aims of this project are to identify specific innate immune receptors including the toll-like receptor family and signaling pathways that are activated by filarial and Wolbachia products and to characterize the early innate immune mechanisms by which the human host recognizes and responds to filarial infections including those mediated by endosymbiotic Wolbachia.